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1 INDICATIONS AND USAGE Sumatriptan injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache. Limitations of Use Use only if a clear diagnosis of migraine or cluster headache has been established. If a patient has no response to the first migraine or cluster headache attack treated with sumatriptan injection, reconsider the diagnosis before sumatriptan injection is administered to treat any subsequent attacks. Sumatriptan injection is not indicated for the prevention of migraine or cluster headache attacks. Sumatriptan injection is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for: Acute treatment of migraine with or without aura in adults. (1) Acute treatment of cluster headache in adults. (1) Limitations of Use Use only if a clear diagnosis of migraine or cluster headache has been established. (1) Not indicated for the prophylactic therapy of migraine or cluster headache attacks. (1)

2 DOSAGE AND ADMINISTRATION For subcutaneous use only. (2.1) Acute treatment of migraine: single dose of 6 mg. (2.1) Acute treatment of cluster headache: single dose of 6 mg. (2.1) Maximum dose in a 24-hour period: 12 mg, separate doses by at least 1 hour. (2.1) 2.1 Dosing Information The maximum single recommended adult dose of sumatriptan injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of migraine, if side effects are dose limiting, lower doses 4 mg may be used [see Clinical Studies (14.1)]. For the treatment of cluster headache, the efficacy of lower doses has not been established. The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg injections separated by at least 1 hour. A second 6-mg dose should only be considered if some response to a first injection was observed. 2.3 Administration Using the Sumatriptan Autoinjector An autoinjector device (Sumatriptan autoinjector) is available for use with 6-mg prefilled syringe to facilitate self-administration in patients using the 6-mg dose. With this device, the needle penetrates approximately 1/4 inch (5 to 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular delivery must be avoided. Instruct patients on the proper use of Sumatriptan autoinjector and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

3 DOSAGE FORMS AND STRENGTHS Injection: 6-mg prefilled syringe assembled in an autoinjector. Each 0.5 mL injection contains 8.4 mg of sumatriptan succinate equivalent to 6 mg of sumatriptan. Sumatriptan injection, USP: 6-mg single-dose prefilled syringe assembled in an autoinjector. (3)

4 CONTRAINDICATIONS Sumatriptan injection is contraindicated in patients with: Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina [see Warnings and Precautions (5.1)]. Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2)]. History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions (5.4)]. Peripheral vascular disease [see Warnings and Precautions (5.5)]. Ischemic bowel disease [see Warnings and Precautions (5.5)]. Uncontrolled hypertension [see Warnings and Precautions (5.8)]. Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine 1 (5-HT 1 ) agonist [see Drug Interactions (7.1, 7.3)]. Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]. Hypersensitivity to sumatriptan injection (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9)]. Severe hepatic impairment [see Clinical Pharmacology (12.3)]. History of coronary artery disease or coronary artery vasospasm. (4) Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders. (4) History of stroke, transient ischemic attack, or hemiplegic or basilar migraine. (4) Peripheral vascular disease. (4) Ischemic bowel disease. (4) Uncontrolled hypertension. (4) Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergotamine-containing medication. (4) Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor. (4) Hypersensitivity to sumatriptan injection (angioedema and anaphylaxis seen). (4) Severe hepatic impairment. (4)

5 WARNINGS AND PRECAUTIONS Myocardial ischemia/infarction and Prinzmetal's angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. (5.1) Arrhythmias: Discontinue sumatriptan injection if occurs. (5.2) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. (5.3) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue sumatriptan injection if occurs. (5.4) Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue sumatriptan injection if occurs. (5.5) Medication overuse headache: Detoxification may be necessary. (5.6) Serotonin syndrome: Discontinue sumatriptan injection if occurs. (5.7) Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. (5.10) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina The use of sumatriptan injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan injection. Some of these reactions occurred in patients without known CAD. Sumatriptan injection may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving sumatriptan injection. If there is evidence of CAD or coronary artery vasospasm, sumatriptan injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of sumatriptan injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of sumatriptan injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of sumatriptan injection. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue sumatriptan injection if these disturbances occur. Sumatriptan injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of sumatriptan injection is contraindicated in patients with CAD and those with Prinzmetal's variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities.

are at high cardiac risk. The use of sumatriptan injection is contraindicated in patients with CAD and those with Prinzmetal's variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue sumatriptan injection if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. Sumatriptan injection is contraindicated in patients with a history of stroke or TIA. 5.5 Other Vasospasm Reactions Sumatriptan injection may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional injections of sumatriptan. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists has not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with sumatriptan injection, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.4)] . Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue sumatriptan injection if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with sumatriptan injection. Sumatriptan injection is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan injection.

tension. Monitor blood pressure in patients treated with sumatriptan injection. Sumatriptan injection is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan injection. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Sumatriptan injection is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan injection. 5.10 Seizures Seizures have been reported following administration of sumatriptan injection. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. Sumatriptan injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Myocardial ischemia, myocardial infarction, and Prinzmetal's angina [see Warnings and Precautions (5.1)] Arrhythmias [see Warnings and Precautions (5.2)] Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)] Cerebrovascular events [see Warnings and Precautions (5.4)] Other vasospasm reactions [see Warnings and Precautions (5.5)] Medication overuse headache [see Warnings and Precautions (5.6)] Serotonin syndrome [see Warnings and Precautions (5.7)] Increase in blood pressure [see Warnings and Precautions (5.8)] Hypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.9)] Seizures [see Warnings and Precautions (5.10)] Most common adverse reactions (≥5% and >placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Migraine Headache Table 1 lists adverse reactions that occurred in 2 U.S. placebo-controlled clinical trials in patients with migraines (Studies 2 and 3) following either a single 6-mg dose of sumatriptan injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with sumatriptan injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) Adverse Reaction Sumatriptan Injection 6 mg Subcutaneous (n = 547) % Placebo (n = 370) % Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort 5 1 Tightness in chest 3 <1 Pressure in chest 2 <1 Ear, nose, and throat Throat discomfort 3 <1 Discomfort: nasal cavity/sinuses 2 <1 Injection site reaction Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. 59 24 Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness 5 <1 Neck pain/stiffness 5 <1 Myalgia 2 <1 Neurological Dizziness/vertigo 12 4 Drowsiness/sedation 3 2 Headache 2 <1 Skin Sweating 2 1 The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Cluster Headache In the controlled clinical trials assessing the efficacy of sumatriptan injection as a treatment for cluster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of sumatriptan injection in patients with migraine. Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials.

luster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of sumatriptan injection in patients with migraine. Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% sumatriptan injection, 0% placebo), nausea and vomiting (4% sumatriptan injection, 0% placebo), and bronchospasm (1% sumatriptan injection, 0% placebo). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sumatriptan tablets, sumatriptan nasal spray, and sumatriptan injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor. Reproductive System and Breast Disorders Breast pain [see Use in Specific Populations (8.2)] .

<table ID="ID53" width="100%" styleCode="Noautorules"><caption>Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3)</caption><col width="41%"/><col width="36%"/><col width="22%"/><tbody><tr><td align="center" styleCode="Lrule Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Adverse Reaction</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg Subcutaneous</content> <content styleCode="bold">(n = 547)</content> <content styleCode="bold">%</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 370)</content> <content styleCode="bold">%</content> </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Atypical sensations </td><td align="center" styleCode=" Rrule" valign="top">42 </td><td align="center" styleCode=" Rrule" valign="top">9 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Tingling </td><td align="center" styleCode=" Rrule" valign="top">14 </td><td align="center" styleCode=" Rrule" valign="top">3 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Warm/hot sensation </td><td align="center" styleCode=" Rrule" valign="top">11 </td><td align="center" styleCode=" Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Burning sensation </td><td align="center" styleCode=" Rrule" valign="top">7 </td><td align="center" styleCode=" Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Feeling of heaviness </td><td align="center" styleCode=" Rrule" valign="top">7 </td><td align="center" styleCode=" Rrule" valign="top">1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Pressure sensation </td><td align="center" styleCode=" Rrule" valign="top">7 </td><td align="center" styleCode=" Rrule" valign="top">2 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Feeling of tightness </td><td align="center" styleCode=" Rrule" valign="top">5 </td><td align="center" styleCode=" Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Numbness </td><td align="center" styleCode=" Rrule" valign="top">5 </td><td align="center" styleCode=" Rrule" valign="top">2 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Feeling strange </td><td align="center" styleCode=" Rrule" valign="top">2 </td><td align="center" styleCode=" Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Tight feeling in head </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Cardiovascular </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Flushing </td><td align="center" styleCode=" Rrule" valign="top">7 </td><td align="center" styleCode=" Rrule" valign="top">2 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Chest discomfort </td><td align="center" styleCode=" Rrule" valign="top">5 </td><td align="center" styleCode=" Rrule" valign="top">1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Tightness in chest </td><td align="center"

top">2 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Chest discomfort </td><td align="center" styleCode=" Rrule" valign="top">5 </td><td align="center" styleCode=" Rrule" valign="top">1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Tightness in chest </td><td align="center" styleCode=" Rrule" valign="top">3 </td><td align="center" styleCode=" Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Pressure in chest </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Ear, nose, and throat </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Throat discomfort </td><td align="center" styleCode=" Rrule" valign="top">3 </td><td align="center" styleCode=" Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Discomfort: nasal cavity/sinuses </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Injection site reaction <footnote ID="ID530">Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding.</footnote> </td><td align="center" styleCode=" Botrule Rrule" valign="top">59 </td><td align="center" styleCode=" Botrule Rrule" valign="top">24 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Miscellaneous </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Jaw discomfort </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Musculoskeletal </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Weakness </td><td align="center" styleCode=" Rrule" valign="top">5 </td><td align="center" styleCode=" Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Neck pain/stiffness </td><td align="center" styleCode=" Rrule" valign="top">5 </td><td align="center" styleCode=" Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Myalgia </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Neurological </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Dizziness/vertigo </td><td align="center" styleCode=" Rrule" valign="top">12 </td><td align="center" styleCode=" Rrule" valign="top">4 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Drowsiness/sedation </td><td align="center" styleCode=" Rrule" valign="top">3 </td><td align="center" styleCode=" Rrule" valign="top">2 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Headache </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Skin </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Sweating </td><td align="c

</td><td align="center" styleCode=" Botrule Rrule" valign="top">&lt;1 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Skin </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Sweating </td><td align="c enter" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1 </td></tr></tbody></table>

7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan injection within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of sumatriptan injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3)] . 7.3 Other 5-HT1 Agonists Because their vasospastic effects may be additive, coadministration of sumatriptan injection and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) 8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal (see Data). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data: The Sumatriptan/Naratriptan/TREXIMET (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group.

edical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Animal Data: Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, respectively. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day. 8.2 Lactation Risk Summary Sumatriptan is excreted in human milk following subcutaneous administration . There are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production. Use of sumatriptan may be associated with transient breast pain [see Adverse Reactions (6.2)] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sumatriptan injection and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition. Clinical Considerations Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan injection. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Sumatriptan injection is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated sumatriptan nasal spray (5 to 20 mg) in 1,248 pediatric migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

neurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan injection (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan injection; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan injection are not presently available. 8.5 Geriatric Use Clinical trials of sumatriptan injection did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving sumatriptan injection [see Warnings and Precautions (5.1)] .

8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal (see Data). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data: The Sumatriptan/Naratriptan/TREXIMET (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group.

edical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Animal Data: Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, respectively. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Sumatriptan injection is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated sumatriptan nasal spray (5 to 20 mg) in 1,248 pediatric migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan injection (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan injection; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan injection are not presently available.

8.5 Geriatric Use Clinical trials of sumatriptan injection did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving sumatriptan injection [see Warnings and Precautions (5.1)] .

10 OVERDOSAGE Coronary vasospasm was observed after intravenous administration of sumatriptan injection [see Contraindications (4)]. Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis. The elimination half-life of sumatriptan is about 2 hours [see Clinical Pharmacology (12.3)]; therefore, monitoring of patients after overdose with sumatriptan injection should continue for at least 10 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

11 DESCRIPTION Sumatriptan Injection, USP contains sumatriptan succinate, a selective 5-HT 1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The empirical formula is C 14 H 21 N 3 O 2 S•C 4 H 6 O 4 , representing a molecular weight of 413.5. Sumatriptan succinate, USP is a white to off-white powder that is readily soluble in water and in saline. Sumatriptan Injection, USP is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of sumatriptan injection, USP 12-mg/mL solution contains 8.4 mg of sumatriptan succinate equivalent to 6 mg of sumatriptan and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of solution is approximately 4.2 to 5.3. The osmolality of the injection is 270-330 mOsmol. Sumatriptan-Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine and cluster headaches through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. 12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)] . Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate. 12.3 Pharmacokinetics Absorption The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (C max ) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T max ) was 12 minutes after injection (range: 5 to 20 minutes) . In this trial, the same dose injected subcutaneously in the thigh gave a C max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T max or amount absorbed was not significantly altered by either the site or technique of injection. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes . Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite. Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes. Specific Populations Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years).

L/min and the terminal half-life was 115 ± 19 minutes. Specific Populations Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Patients with Hepatic Impairment: The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan injection in this population is contraindicated [see Contraindications (4)] . Racial Groups: The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Drug Interaction Studies Monoamine Oxidase-A Inhibitors: In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine and cluster headaches through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)] . Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

12.3 Pharmacokinetics Absorption The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (C max ) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T max ) was 12 minutes after injection (range: 5 to 20 minutes) . In this trial, the same dose injected subcutaneously in the thigh gave a C max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T max or amount absorbed was not significantly altered by either the site or technique of injection. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes . Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite. Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes. Specific Populations Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Patients with Hepatic Impairment: The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan injection in this population is contraindicated [see Contraindications (4)] . Racial Groups: The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Drug Interaction Studies Monoamine Oxidase-A Inhibitors: In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose to mice and rats was approximately 130 and 260 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m 2 basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration. Mutagenesis Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both. When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day. 13.2 Animal Toxicology and/or Pharmacology Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative plasma exposure at the lowest dose tested was approximately 3 times the human exposure after a 6-mg subcutaneous dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose to mice and rats was approximately 130 and 260 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m 2 basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration. Mutagenesis Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both. When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day.

13.2 Animal Toxicology and/or Pharmacology Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative plasma exposure at the lowest dose tested was approximately 3 times the human exposure after a 6-mg subcutaneous dose.

14 CLINICAL STUDIES 14.1 Migraine In controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6-mg sumatriptan injection. Lower doses of sumatriptan injection may also prove effective, although the proportion of patients obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. In Study 1, 6 different doses of sumatriptan injection (n = 30 each group) were compared with placebo (n = 62) in a single-attack, parallel-group design; the dose-response relationship was found to be as shown in Table 2. Table 2. Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Dose of Sumatriptan in Study 1 a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. Dose of Sumatriptan Injection Percent Patients with Relief a Adverse Reactions Incidence (%) at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours Placebo 5 15 24 21 55 1 mg 10 40 43 40 63 2 mg 7 23 57 43 63 3 mg 17 47 57 60 77 4 mg 13 37 50 57 80 6 mg 10 63 73 70 83 8 mg 23 57 80 83 93 In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 patients with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6-mg subcutaneous dose of sumatriptan injection. Approximately 82% and 65% of patients treated with sumatriptan injection 6 mg had headache relief and were pain free within 2 hours, respectively. Table 3 shows the 1- and 2-hour efficacy results for sumatriptan injection 6 mg in Studies 2 and 3. Table 3. Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3 a P <0.05 versus placebo. b A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. c Includes patients that may have received an additional placebo injection 1 hour after the initial injection. d Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection. 1-Hour Data Study 2 Study 3 Placebo (n = 190) Sumatriptan Injection 6 mg (n = 384) Placebo (n = 180) Sumatriptan Injection 6 mg (n = 350) Patients with pain relief (Grade 0/1) 18% 70% a 26% 70% a Patients with no pain 5% 48% a 13% 49% a Patients without nausea 48% 73% a 50% 73% a Patients without photophobia 23% 56% a 25% 58% a Patients with little or no clinical disability b 34% 76% a 34% 76% a 2-Hour Data Study 2 Study 3 Placebo c Sumatriptan Injection 6 mg d Placebo c Sumatriptan Injection 6 mg d Patients with pain relief (Grade 0/1) 31% 81% a 39% 82% a Patients with no pain 11% 63% a 19% 65% a Patients without nausea 56% 82% a 63% 81% a Patients without photophobia 31% 72% a 35% 71% a Patients with little or no clinical disability b 42% 85% a 49% 84% a Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.

n 11% 63% a 19% 65% a Patients without nausea 56% 82% a 63% 81% a Patients without photophobia 31% 72% a 35% 71% a Patients with little or no clinical disability b 42% 85% a 49% 84% a Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. Similar efficacy was seen when patients self-administered Sumatriptan injection using sumatriptan injection prefilled syringe or sumatriptan autoinjector. The efficacy of sumatriptan injection was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers). 14.2 Cluster Headache The efficacy of sumatriptan injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials (Studies 4 and 5). Patients aged 21 to 65 years were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a reduction in headache severity to mild or no pain. In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of sumatriptan injection compared with those who received placebo (see Table 4). Table 4. Proportion of Patients with Cluster Headache Relief by Time in Studies 4 and 5 n = Number of headaches treated. Study 4 Study 5 Placebo (n = 39) Sumatriptan Injection 6 mg (n = 39) Placebo (n = 88) Sumatriptan Injection 6 mg (n = 92) Patients with pain relief (no/mild) 5 Minutes post-injection 8% 21% 7% 23% P <0.05. 10 Minutes post-injection 10% 49% 25% 49% 15 Minutes post-injection 26% 74% 35% 75% An estimate of the cumulative probability of a patient with a cluster headache obtaining relief after being treated with either sumatriptan injection or placebo is presented in Figure 1. Figure 1. Time to Relief of Cluster Headache from Time of Injection a a The figure uses Kaplan-Meier (product limit) Survivorship Plot. Patients taking rescue medication were censored at 15 minutes. The plot was constructed with data from patients who either experienced relief or did not require (request) rescue medication within a period of 2 hours following treatment. As a consequence, the data in the plot are derived from only a subset of the 258 headaches treated (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 headaches treated with sumatriptan injection). Other data suggest that treatment with sumatriptan injection is not associated with an increase in early recurrence of headache and has little effect on the incidence of later-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours). Time to Relief of Cluster Headache from Time of Injectiona

<table ID="ID100" width="100%" styleCode="Noautorules"><caption>Table 2. Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Dose of Sumatriptan in Study 1</caption><col width="21%"/><col width="14%"/><col width="17%"/><col width="14%"/><col width="15%"/><col width="17%"/><tfoot><tr><td align="left" colspan="6"><paragraph styleCode="Footnote">^aRelief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication.

><col width="21%"/><col width="14%"/><col width="17%"/><col width="14%"/><col width="15%"/><col width="17%"/><tfoot><tr><td align="left" colspan="6"><paragraph styleCode="Footnote">^aRelief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" styleCode="Lrule Toprule Botrule Rrule"><content styleCode="bold">Dose of Sumatriptan Injection</content> </td><td colspan="4" align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Percent Patients with Relief ^a</content> </td><td rowspan="2" align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Adverse Reactions Incidence (%)</content> </td></tr><tr><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">at 10 Minutes</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">at 30 Minutes</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">at 1 Hour</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">at 2 Hours</content> </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Placebo </td><td align="center" styleCode=" Rrule" valign="top">5 </td><td align="center" styleCode=" Rrule" valign="top">15 </td><td align="center" styleCode=" Rrule" valign="top">24 </td><td align="center" styleCode=" Rrule" valign="top">21 </td><td align="center" styleCode=" Rrule" valign="top">55 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">1 mg </td><td align="center" styleCode=" Rrule" valign="top">10 </td><td align="center" styleCode=" Rrule" valign="top">40 </td><td align="center" styleCode=" Rrule" valign="top">43 </td><td align="center" styleCode=" Rrule" valign="top">40 </td><td align="center" styleCode=" Rrule" valign="top">63 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">2 mg </td><td align="center" styleCode=" Rrule" valign="top">7 </td><td align="center" styleCode=" Rrule" valign="top">23 </td><td align="center" styleCode=" Rrule" valign="top">57 </td><td align="center" styleCode=" Rrule" valign="top">43 </td><td align="center" styleCode=" Rrule" valign="top">63 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">3 mg </td><td align="center" styleCode=" Rrule" valign="top">17 </td><td align="center" styleCode=" Rrule" valign="top">47 </td><td align="center" styleCode=" Rrule" valign="top">57 </td><td align="center" styleCode=" Rrule" valign="top">60 </td><td align="center" styleCode=" Rrule" valign="top">77 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">4 mg </td><td align="center" styleCode=" Rrule" valign="top">13 </td><td align="center" styleCode=" Rrule" valign="top">37 </td><td align="center" styleCode=" Rrule" valign="top">50 </td><td align="center" styleCode=" Rrule" valign="top">57 </td><td align="center" styleCode=" Rrule" valign="top">80 </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">6 mg </td><td align="center" styleCode=" Rrule" valign="top">10 </td><td align="center" styleCode=" Rrule" valign="top">63 </td><td align="center" styleCode=" Rrule" valign="top">73 </td><td align="center" styleCode=" Rrule" valign="top">70 </td><td align="center" styleCode=" Rrule" valign="top">83 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">8 mg </td><td align="center" styleCode=" Botrule Rrule" valign="top">23 </td><td align="center" styleCode=" Botrule Rrule" valign="top">57 </td><td align="center" styleCode=" Botrule Rrule" valign="top">80 </td><td align="center" styleCode=" Botrule Rrule" valign="top">83 </td><td align="center" styleCode=" Botr

="top">8 mg </td><td align="center" styleCode=" Botrule Rrule" valign="top">23 </td><td align="center" styleCode=" Botrule Rrule" valign="top">57 </td><td align="center" styleCode=" Botrule Rrule" valign="top">80 </td><td align="center" styleCode=" Botrule Rrule" valign="top">83 </td><td align="center" styleCode=" Botr ule Rrule" valign="top">93 </td></tr></tbody></table> <table ID="ID102" width="103%" styleCode="Noautorules"><caption>Table 3. Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3</caption><col width="38%"/><col width="13%"/><col width="18%"/><col width="11%"/><col width="18%"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^a<content styleCode="italics">P</content>&lt;0.05 versus placebo. </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^bA successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^cIncludes patients that may have received an additional placebo injection 1 hour after the initial injection. </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^dIncludes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection.

patients that may have received an additional placebo injection 1 hour after the initial injection. </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^dIncludes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="center" styleCode="Lrule Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">1-Hour Data</content> </td><td colspan="2" align="center" styleCode=" Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Study 2</content> </td><td colspan="2" align="center" styleCode=" Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Study 3</content> </td></tr><tr><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 190)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg</content> <content styleCode="bold">(n = 384)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 180)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg</content> <content styleCode="bold">(n = 350)</content> </td></tr><tr><td align="left" styleCode=" Lrule Rrule">Patients with pain relief (Grade 0/1) </td><td align="center" styleCode=" Rrule">18% </td><td align="center" styleCode=" Rrule">70% ^a </td><td align="center" styleCode=" Rrule">26% </td><td align="center" styleCode=" Rrule">70% ^a </td></tr><tr><td align="left" styleCode=" Lrule Rrule">Patients with no pain </td><td align="center" styleCode=" Rrule">5% </td><td align="center" styleCode=" Rrule">48% ^a </td><td align="center" styleCode=" Rrule">13% </td><td align="center" styleCode=" Rrule">49% ^a </td></tr><tr><td align="left" styleCode=" Lrule Rrule">Patients without nausea </td><td align="center" styleCode=" Rrule">48% </td><td align="center" styleCode=" Rrule">73% ^a </td><td align="center" styleCode=" Rrule">50% </td><td align="center" styleCode=" Rrule">73% ^a </td></tr><tr><td align="left" styleCode=" Lrule Rrule">Patients without photophobia </td><td align="center" styleCode=" Rrule">23% </td><td align="center" styleCode=" Rrule">56% ^a </td><td align="center" styleCode=" Rrule">25% </td><td align="center" styleCode=" Rrule">58% ^a </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Patients with little or no clinical disability ^b </td><td align="center" styleCode=" Botrule Rrule">34% </td><td align="center" styleCode=" Botrule Rrule">76% ^a </td><td align="center" styleCode=" Botrule Rrule">34% </td><td align="center" styleCode=" Botrule Rrule">76% ^a </td></tr><tr><td rowspan="2" align="center" styleCode="Lrule Botrule Rrule" valign="bottom"><content styleCode="bold">2-Hour Data</content> </td><td colspan="2" align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Study 2</content> </td><td colspan="2" align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold"> Study 3</content> </td></tr><tr><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Placebo ^c</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg ^d</content> </td><td align="center" styleCode=" Botrule Rrule" val

otrule Rrule" valign="bottom"><content styleCode="bold">Placebo ^c</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg ^d</content> </td><td align="center" styleCode=" Botrule Rrule" val ign="bottom"><content styleCode="bold">Placebo ^c</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg ^d</content> </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Patients with pain relief (Grade 0/1) </td><td align="center" styleCode=" Rrule">31% </td><td align="center" styleCode=" Rrule">81% ^a </td><td align="center" styleCode=" Rrule">39% </td><td align="center" styleCode=" Rrule">82% ^a </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Patients with no pain </td><td align="center" styleCode=" Rrule">11% </td><td align="center" styleCode=" Rrule">63% ^a </td><td align="center" styleCode=" Rrule">19% </td><td align="center" styleCode=" Rrule">65% ^a </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Patients without nausea </td><td align="center" styleCode=" Rrule">56% </td><td align="center" styleCode=" Rrule">82% ^a </td><td align="center" styleCode=" Rrule">63% </td><td align="center" styleCode=" Rrule">81% ^a </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Patients without photophobia </td><td align="center" styleCode=" Rrule">31% </td><td align="center" styleCode=" Rrule">72% ^a </td><td align="center" styleCode=" Rrule">35% </td><td align="center" styleCode=" Rrule">71% ^a </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Patients with little or no clinical disability ^b </td><td align="center" styleCode=" Botrule Rrule">42% </td><td align="center" styleCode=" Botrule Rrule">85% ^a </td><td align="center" styleCode=" Botrule Rrule">49% </td><td align="center" styleCode=" Botrule Rrule">84% ^a </td></tr></tbody></table>

h little or no clinical disability ^b </td><td align="center" styleCode=" Botrule Rrule">42% </td><td align="center" styleCode=" Botrule Rrule">85% ^a </td><td align="center" styleCode=" Botrule Rrule">49% </td><td align="center" styleCode=" Botrule Rrule">84% ^a </td></tr></tbody></table> <table ID="ID106" width="100%" styleCode="Noautorules"><caption>Table 4. Proportion of Patients with Cluster Headache Relief by Time in Studies 4 and 5</caption><col width="38%"/><col width="12%"/><col width="17%"/><col width="13%"/><col width="17%"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">n = Number of headaches treated.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Lrule Toprule Botrule Rrule" valign="top"/><td colspan="2" align="center" styleCode=" Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Study 4</content> </td><td colspan="2" align="center" styleCode=" Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Study 5</content> </td></tr><tr><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 39)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg</content> <content styleCode="bold">(n = 39)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 88)</content> </td><td align="center" styleCode=" Botrule Rrule" valign="bottom"><content styleCode="bold">Sumatriptan Injection</content> <content styleCode="bold">6 mg</content> <content styleCode="bold">(n = 92)</content> </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">Patients with pain relief (no/mild) </td><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/><td styleCode=" Rrule" valign="top"/></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">5 Minutes post-injection </td><td align="center" styleCode=" Rrule" valign="top">8% </td><td align="center" styleCode=" Rrule" valign="top">21% </td><td align="center" styleCode=" Rrule" valign="top">7% </td><td align="center" styleCode=" Rrule" valign="top">23% <footnote ID="ID1060">P &lt;0.05. </footnote> </td></tr><tr><td align="left" styleCode=" Lrule Rrule" valign="top">10 Minutes post-injection </td><td align="center" styleCode=" Rrule" valign="top">10% </td><td align="center" styleCode=" Rrule" valign="top">49% <footnoteRef IDREF="ID1060"/> </td><td align="center" styleCode=" Rrule" valign="top">25% </td><td align="center" styleCode=" Rrule" valign="top">49% <footnoteRef IDREF="ID1060"/> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">15 Minutes post-injection </td><td align="center" styleCode=" Botrule Rrule" valign="top">26% </td><td align="center" styleCode=" Botrule Rrule" valign="top">74% <footnoteRef IDREF="ID1060"/> </td><td align="center" styleCode=" Botrule Rrule" valign="top">35% </td><td align="center" styleCode=" Botrule Rrule" valign="top">75% <footnoteRef IDREF="ID1060"/> </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Sumatriptan injection, USP contains sumatriptan (base) as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows: Autoinjector: Each pack contains a patient information and instructions for use leaflet. Sumatriptan Injection USP, 6 mg, containing 2 prefilled syringes assembled in an autoinjector per carton (51407-673-02) Store between 2° and 30°C (36° and 86°F). Protect from light.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events Inform patients that sumatriptan injection may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)]. Hypersensitivity Reactions Inform patients that anaphylactic reactions have occurred in patients receiving sumatriptan injection. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4), Warnings and Precautions (5.9)]. Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of sumatriptan injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.3)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the use of sumatriptan injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7), Drug Interactions (7.4)]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations (8.1)] . Lactation Advise breastfeeding women that they may develop transient breast pain when taking sumatriptan injection. Advise breastfeeding women that avoiding breastfeeding for 12 hours after treatment with sumatriptan injection can minimize their infant's exposure to sumatriptan [see Use in Specific Populations (8.2)] . Ability to Perform Complex Tasks Treatment with sumatriptan injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of sumatriptan injection. How to Use Sumatriptan Injection Instruct patients to read the Instructions for Use before starting therapy. Provide patients instruction on the proper use of sumatriptan injection if they are able to self-administer sumatriptan injection in medically unsupervised situations. Instruct patients on storage and disposal of the autoinjector [see How Supplied/Storage and Handling (16)] . Inform patients that the needle in the sumatriptan autoinjector penetrates approximately 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given subcutaneously and intramuscular or intravascular delivery should be avoided.

of the autoinjector [see How Supplied/Storage and Handling (16)] . Inform patients that the needle in the sumatriptan autoinjector penetrates approximately 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. Manufactured by: OneSource Specialty Pharma Limited Bengaluru - 560076, India. Distributed by: Strides Pharma Inc. Bridgewater, NJ 08807 January 2026 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA

PATIENT INFORMATION Sumatriptan (soo-ma-trip-tan) Injection USP What is the most important information I should know about sumatriptan injection? Sumatriptan injection can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking sumatriptan injection and get emergency medical help right away if you have any of the following symptoms of a heart attack: discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw pain or discomfort in your arms, back, neck, jaw, or stomach shortness of breath with or without chest discomfort breaking out in a cold sweat nausea or vomiting feeling lightheaded Sumatriptan injection is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you: have high blood pressure have high cholesterol levels smoke are overweight have diabetes have a family history of heart disease What is sumatriptan injection? Sumatriptan injection is a prescription medicine used to treat acute migraine headaches with or without aura and acute cluster headaches in adults who have been diagnosed with migraine or cluster headaches. Sumatriptan is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines. Sumatriptan is not used to prevent or decrease the number of migraine or cluster headaches you have. It is not known if sumatriptan is safe and effective in children under 18 years of age. Do not take sumatriptan injection if you have: heart problems or a history of heart problems. narrowing of blood vessels to your legs, arms, stomach, or kidneys (peripheral vascular disease). uncontrolled high blood pressure. severe liver problems. hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider. had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation. taken any of the following medicines in the last 24 hours: almotriptan (AXERT) eletriptan (RELPAX) frovatriptan (FROVA) naratriptan (AMERGE) rizatriptan (MAXALT, MAXALT-MLT) sumatriptan and naproxen (TREXIMET) ergotamines (CAFERGOT, ERGOMAR, MIGERGOT) dihydroergotamine (D.H.E.45, MIGRANAL) Ask your healthcare provider if you are not sure if your medicine is listed above. an allergy to sumatriptan or any of the ingredients in sumatriptan injection. See the end of this leaflet for a complete list of ingredients in sumatriptan injection. Before taking sumatriptan injection, tell your healthcare provider about all of your medical conditions, including if you: have high blood pressure have high cholesterol have diabetes smoke are overweight have heart problems or family history of heart problems or stroke have kidney problems have liver problems are allergic to latex have had epilepsy or seizures are not using effective birth control are pregnant or plan to become pregnant. It is not known if sumatriptan can harm your unborn baby. are breastfeeding or plan to breastfeed. Sumatriptan passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take sumatriptan.

e pregnant or plan to become pregnant. It is not known if sumatriptan can harm your unborn baby. are breastfeeding or plan to breastfeed. Sumatriptan passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take sumatriptan. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Sumatriptan and certain other medicines can affect each other, causing serious side effects. Especially tell your healthcare provider if you take antidepressant medicines called: selective serotonin reuptake inhibitors (SSRIs) serotonin norepinephrine reuptake inhibitors (SNRIs) tricyclic antidepressants (TCAs) monoamine oxidase inhibitors (MAOIs) Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I take sumatriptan injection? Certain people should take their first dose of sumatriptan injection in their healthcare provider's office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting. Use sumatriptan injection exactly as your healthcare provider tells you to use it. Your healthcare provider may change your dose. Do not change your dose without first talking with your healthcare provider. For adults, the usual dose is a single injection given just below the skin. You should give an injection as soon as the symptoms of your headache start, but it may be given at any time during a migraine or cluster headache attack. If you did not get any relief after the first injection, do not give a second injection without first talking with your healthcare provider. If your headache comes back or you only get some relief after your first injection, you can take a second injection 1 hour after the first injection, but not sooner. Do not take more than 12 mg in a 24-hour period. If you use too much sumatriptan injection, call your healthcare provider or go to the nearest hospital emergency room right away. You should write down when you have headaches and when you take sumatriptan injection so you can talk with your healthcare provider about how sumatriptan injection is working for you. What should I avoid while taking sumatriptan injection? Sumatriptan can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert. What are the possible side effects of sumatriptan injection? Sumatriptan may cause serious side effects. See "What is the most important information I should know about sumatriptan injection?" These serious side effects include: changes in color or sensation in your fingers and toes (Raynaud's syndrome) stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include: sudden or severe stomach pain nausea or vomiting stomach pain after meals constipation or diarrhea weight loss bloody diarrhea fever problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include: cramping and pain in your legs or hips feeling of heaviness or tightness in your leg muscles burning or aching pain in your feet or toes while resting numbness, tingling, or weakness in your legs cold feeling or color changes in 1 or both legs or feet medication overuse headaches. Some people who use too many sumatriptan injections may have worse headaches (medication overuse headache).

ess in your leg muscles burning or aching pain in your feet or toes while resting numbness, tingling, or weakness in your legs cold feeling or color changes in 1 or both legs or feet medication overuse headaches. Some people who use too many sumatriptan injections may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with sumatriptan. serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using sumatriptan injection, especially if sumatriptan injection is used with anti-depressant medicines called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome: mental changes such as seeing things that are not there (hallucinations), agitation, or coma fast heartbeat changes in blood pressure high body temperature tight muscles trouble walking ● hives (itchy bumps); swelling of your tongue, mouth or throat. ● seizures. Seizures have happened in people taking sumatriptan injection who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take sumatriptan injection. The most common side effects of sumatriptan injection include: pain or redness at your injection site tingling or numbness in your fingers or toes dizziness warm, hot, burning feeling to your face (flushing) discomfort or stiffness in your neck feeling weak, drowsy, or tired Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of sumatriptan injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store sumatriptan injection? Store sumatriptan between 36°F to 86°F (2°C to 30°C). Store your medicine away from light. Keep your medicine in the packaging. Keep sumatriptan injection and all medicines out of the reach of children. General information about the safe and effective use of sumatriptan injection Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use sumatriptan injection for a condition for which it was not prescribed. Do not give sumatriptan injection to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about sumatriptan injection. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about sumatriptan injection that is written for healthcare professionals. For more information, contact Strides pharma Inc at 1-877-244-9825. What are the ingredients in Sumatriptan Injection? Active ingredient: sumatriptan succinate Inactive ingredients: sodium chloride, water for injection, Nitrogen Trade names are the property of their respective owners. Manufactured by: OneSource Specialty Pharma Limited Bengaluru - 560076, India. Distributed by: Strides Pharma Inc. Bridgewater, NJ 08807 January 2026 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA

INSTRUCTIONS FOR USE SECTION Read this Patient Instructions for Use before you start to use Sumatriptan Autoinjector System. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about sumatriptan injection when you start taking it and at regular checkups. • Use the device immediately once the cap has been removed; it is advised not to postpone the injection. • Keep the Sumatriptan Autoinjector System out of the reach of children. INSTRUCTIONS FOR USE OF SUMATRIPTAN AUTOINJECTOR Important things that you need to know This device is called an Sumatriptan autoinjector. Here we use the shorter name 'autoinjector'. 1. Read all of the instructions carefully before using this autoinjector. 2. Follow these step-by-step instructions every time you use the autoinjector, ask your doctor or pharmacist. 3. Only use each autoinjector once - do not try to use more than once. ABOUT THE AUTOINJECTOR The parts of the Autoinjector are shown in this picture 1 GETTING READY 1.1 Wash your hands. 1.2 Choose an area with an adequate fatty tissue layer usually the outside of the thigh. 1.3 Clean the skin area to be injected with alcohol or a new sterile swab (see Figure A). 1.4 Take the Sumatriptan Autoinjector out of the package. 1.5 Look in the medicine window on the autoinjector. • Before injection, to check that the liquid is clear (see Figure B) . • If it is difficult to see what is in the window, hold the autoinjector upto the light and check. • After injection, the blue plunger rod completely fills the medicine window (see Figure C) . • If the blue plunger rod can be seen through the medicine window, the device is spent and cannot be used again. 1.6 Pull the gray cap off the autoinjector. • Do not twist the cap. • Pull it straight off (see Figure D) 1.7 Look inside the cap, check that the gray needle cover is inside (see Figure E). Do not use the autoinjector if the gray needle cover is not inside the cap. 1.8 Do not try to put the cap back. If you try to put it back, this will damage the needle . You are now ready to inject the medicine, go to step 2.1. 2 INJECTING THE MEDICINE 2. Without pressing the blue button, push the autoinjector firmly against your skin until you feel the stop point (see Figure F). • Pushing to the stop point unlocks the button. • As long as the autoinjector is firmly pressed against the skin, the safety lock is deactivated; the autoinjector could fire unintentionally if the blue button is pressed by accident. • Do not attempt to re-engage the safety lock at any time • Keep the autoinjector pressed against your skin for the next steps. 2.2 Keep pushing the autoinjector against your skin then firmly press down the blue button on the top of the autoinjector until it will not go further (see Figure G). • You will hear a click, this indicates that the injection has started (see Figure G) . • If the injection did not start, release the blue button, make sure the autoinjector is pushed down against the skin and push down harder on the blue button. 2.3 Do not take the autoinjector off your skin. • Monitor the injection through the medicine window to make sure that the entire dose is injected. The blue plunger will move down the window, completely fill it, and stop moving when the injection is done (see Figure H) .

the skin and push down harder on the blue button. 2.3 Do not take the autoinjector off your skin. • Monitor the injection through the medicine window to make sure that the entire dose is injected. The blue plunger will move down the window, completely fill it, and stop moving when the injection is done (see Figure H) . • When the injection is done, keep holding the autoinjector against the skin for 5 seconds (see Figure I) . If you take the autoinjector off before, not all of the medicine will be injected. 2.4 Carefully take the Autoinjector off your skin (see Figure J). • The protective sleeve automatically covers the needle. It is then locked and the needle is protected. 3 WHAT TO DO AFTER THE INJECTION 3.1 If you notice a spot of blood at the injection site, dab away with a cotton ball or tissue paper. Do not rub the injection site. If needed, you may cover the injection site with a bandage. 3.2 Visually check that there is no liquid left at the bottom of the medicine window. If there is liquid, consult your doctor or pharmacist. 4 DISPOSE THE AUTOINJECTOR 4.1 Discard the whole Sumatriptan Autoinjector after use and discard the cap. • Put your used injection Autoinjector in a FDA-cleared sharps disposal container right away after use (see Figure K) . If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and cartridges. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Do not try to reuse the autoinjector. To avoid any injury, never try to touch the needle. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. To reorder additional Patient information sheets contact Strides pharma Inc at 1-877-244-9825 Rx Only Manufactured by: OneSource Specialty Pharma Limited Bengaluru - 560076, India. Distributed by: Strides Pharma Inc. Bridgewater, NJ 08807 Revised: 01/2026 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA device image image description Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K

1 INDICATIONS AND USAGE IMITREX tablets are indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: • Use only if a clear diagnosis of migraine headache has been established. If a patient has no response to the first migraine attack treated with IMITREX, reconsider the diagnosis of migraine before IMITREX is administered to treat any subsequent attacks. • IMITREX is not indicated for the prevention of migraine attacks. • Safety and effectiveness of IMITREX tablets have not been established for cluster headache. IMITREX is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for acute treatment of migraine with or without aura in adults. ( 1 ) Limitations of Use: • Use only if a clear diagnosis of migraine headache has been established. ( 1 ) • Not indicated for the prophylactic therapy of migraine attacks. ( 1 ) • Not indicated for the treatment of cluster headache. ( 1 )

2 DOSAGE AND ADMINISTRATION • Single dose of 25-mg, 50-mg, or 100-mg tablet. ( 2.1 ) • A second dose should only be considered if some response to the first dose was observed. Separate doses by at least 2 hours. ( 2.1 ) • Maximum dose in a 24-hour period: 200 mg. ( 2.1 ) • Maximum single dose should not exceed 50 mg in patients with mild to moderate hepatic impairment. ( 2.2 ) 2.1 Dosing Information The recommended dose of IMITREX tablets is 25 mg, 50 mg, or 100 mg. Doses of 50 mg and 100 mg may provide a greater effect than the 25-mg dose, but doses of 100 mg may not provide a greater effect than the 50-mg dose. Higher doses may have a greater risk of adverse reactions [see Clinical Studies (14)] . If the migraine has not resolved by 2 hours after taking IMITREX tablets, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 200 mg in a 24-hour period. Use after IMITREX Injection If the migraine returns following an initial treatment with IMITREX (sumatriptan) injection, additional single IMITREX tablets (up to 100 mg/day) may be given with an interval of at least 2 hours between tablet doses. The safety of treating an average of more than 4 headaches in a 30-day period has not been established. 2.2 Dosing in Patients with Hepatic Impairment If treatment is deemed advisable in the presence of mild to moderate hepatic impairment, the maximum single dose should not exceed 50 mg [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .

3 DOSAGE FORMS AND STRENGTHS 25-mg Tablets: White, triangular-shaped, film-coated, and debossed with “I” on one side and “25” on the other. Each tablet contains 35 mg of sumatriptan succinate equivalent to 25 mg of sumatriptan. 50-mg Tablets: White, triangular-shaped, film-coated, and debossed with “IMITREX 50” on one side and a chevron shape (^) on the other. Each tablet contains 70 mg of sumatriptan succinate equivalent to 50 mg of sumatriptan. 100-mg Tablets: Pink, triangular-shaped, film-coated, and debossed with “IMITREX 100” on one side and a chevron shape (^) on the other. Each tablet contains 140 mg of sumatriptan succinate equivalent to 100 mg of sumatriptan. Tablets: 25 mg, 50 mg, and 100 mg ( 3 )

4 CONTRAINDICATIONS IMITREX Tablets are contraindicated in patients with: • Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina [see Warnings and Precautions (5.1)] • Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2)] • History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions (5.4)] • Peripheral vascular disease [see Warnings and Precautions (5.5)] • Ischemic bowel disease [see Warnings and Precautions (5.5)] • Uncontrolled hypertension [see Warnings and Precautions (5.8)] • Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine 1 (5-HT 1 ) agonist [see Drug Interactions (7.1, 7.3)] • Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2), Clinical Pharmacology (12.3)] • Hypersensitivity to IMITREX (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9)] • Severe hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] • History of coronary artery disease or coronary artery vasospasm ( 4 ) • Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders ( 4 ) • History of stroke, transient ischemic attack, or hemiplegic or basilar migraine ( 4 ) • Peripheral vascular disease ( 4 ) • Ischemic bowel disease ( 4 ) • Uncontrolled hypertension ( 4 ) • Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergotamine-containing medication ( 4 ) • Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor ( 4 ) • Hypersensitivity to IMITREX (angioedema and anaphylaxis seen) ( 4 ) • Severe hepatic impairment ( 4 )

5 WARNINGS AND PRECAUTIONS • Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. ( 5.1 ) • Arrhythmias: Discontinue IMITREX if occurs. ( 5.2 ) • Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. ( 5.3 ) • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs. ( 5.4 ) • Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue IMITREX if occurs. ( 5.5 ) • Medication overuse headache: Detoxification may be necessary. ( 5.6 ) • Serotonin syndrome: Discontinue IMITREX if occurs. ( 5.7 ) • Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. ( 5.10 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina The use of IMITREX tablets is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of IMITREX tablets. Some of these reactions occurred in patients without known CAD. IMITREX tablets may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX tablets. If there is evidence of CAD or coronary artery vasospasm, IMITREX tablets are contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of IMITREX tablets in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of IMITREX tablets. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX tablets. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue IMITREX tablets if these disturbances occur. IMITREX tablets are contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with IMITREX tablets and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of IMITREX tablets is contraindicated in patients with CAD and those with Prinzmetal’s variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not.

red in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX tablets if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neurological conditions. IMITREX tablets are contraindicated in patients with a history of stroke or TIA. 5.5 Other Vasospasm Reactions IMITREX tablets may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional IMITREX tablets. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5‑HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists has not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with IMITREX tablets, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.4)] . Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue IMITREX tablets if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with IMITREX. IMITREX tablets are contraindicated in patients with uncontrolled hypertension. 5.9 Anaphylactic/Anaphylactoid Reactions Anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. IMITREX tablets are contraindicated in patients with a history of hypersensitivity reaction to IMITREX.

in patients receiving IMITREX. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. IMITREX tablets are contraindicated in patients with a history of hypersensitivity reaction to IMITREX. 5.10 Seizures Seizures have been reported following administration of IMITREX. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. IMITREX tablets should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: • Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and Precautions (5.1)] • Arrhythmias [see Warnings and Precautions (5.2)] • Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)] • Cerebrovascular events [see Warnings and Precautions (5.4)] • Other vasospasm reactions [see Warnings and Precautions (5.5)] • Medication overuse headache [see Warnings and Precautions (5.6)] • Serotonin syndrome [see Warnings and Precautions (5.7)] • Increase in blood pressure [see Warnings and Precautions (5.8)] • Hypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.9)] • Seizures [see Warnings and Precautions (5.10)] Most common adverse reactions (≥2% and >placebo) were paresthesia, warm/cold sensation, chest pain/tightness/pressure and/or heaviness, neck/throat/jaw pain/tightness/pressure, other sensations of pain/pressure/tightness/heaviness, vertigo, and malaise/fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 lists adverse reactions that occurred in placebo-controlled clinical trials in patients who took at least 1 dose of study drug. Only treatment-emergent adverse reactions that occurred at a frequency of 2% or more in any group treated with IMITREX tablets and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1. Adverse Reactions Reported by at Least 2% of Patients Treated with IMITREX Tablets and at a Greater Frequency than Placebo Adverse Reaction Percent of Patients Reporting IMITREX Tablets 25 mg (n = 417) IMITREX Tablets 50 mg (n = 771) IMITREX Tablets 100 mg (n = 437) Placebo (n = 309) Atypical sensations 5 6 6 4 Paresthesia (all types) 3 5 3 2 Sensation warm/cold 3 2 3 2 Pain and other pressure sensations 6 6 8 4 Chest - pain/tightness/ pressure and/or heaviness 1 2 2 1 Neck/throat/jaw - pain/ tightness/pressure <1 2 3 <1 Pain - location specified 2 1 1 1 Other - pressure/tightness/ heaviness 1 1 3 2 Neurological Vertigo <1 <1 2 <1 Other Malaise/fatigue 2 2 3 <1 The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of IMITREX tablets, IMITREX nasal spray, and IMITREX injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to IMITREX or a combination of these factors. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor. Reproductive System and Breast Disorders Breast pain [see Use in Specific Populations ( 8.2 )] .

<table width="100%"><col width="24%"/><col width="22%"/><col width="20%"/><col width="18%"/><col width="15%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="4" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Percent of Patients Reporting</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">IMITREX Tablets</content> <content styleCode="bold">25 mg</content> <content styleCode="bold">(n = 417)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">IMITREX Tablets</content> <content styleCode="bold">50 mg</content> <content styleCode="bold">(n = 771)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">IMITREX Tablets</content> <content styleCode="bold">100 mg</content> <content styleCode="bold">(n = 437)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 309)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Atypical sensations</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Paresthesia (all types)</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Sensation warm/cold</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Pain and other pressure sensations</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Chest - pain/tightness/ pressure and/or heaviness</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></

<td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Chest - pain/tightness/ pressure and/or heaviness</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></ td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Neck/throat/jaw - pain/ tightness/pressure</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Pain - location specified</item></list></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Other - pressure/tightness/ heaviness</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Neurological</paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption> </caption>Vertigo</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Other</paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item><caption> </caption>Malaise/fatigue</item></list></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;1</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and IMITREX tablets within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO‑A inhibitors increase systemic exposure by 7-fold. Therefore, the use of IMITREX tablets in patients receiving MAO‑A inhibitors is contraindicated [see Clinical Pharmacology (12.3)] . 7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, coadministration of IMITREX tablets and other 5‑HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal (see Data) . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data: The Sumatriptan/Naratriptan/TREXIMET (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group.

edical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Animal Data: Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 (approximately 2 times the MRHD on a mg/m 2 basis) and 0.75 mg/kg/day, respectively. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 2 times the MRHD on a mg/m 2 basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 3 times the MRHD on a mg/m 2 basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 5 times the MRHD on a mg/m 2 basis. 8.2 Lactation Risk Summary Sumatriptan is excreted in human milk following subcutaneous administration. There is no information regarding sumatriptan concentrations in milk from lactating women following administration of IMITREX tablets. There are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production. Use of sumatriptan may be associated with transient breast pain [see Adverse Reactions ( 6.2 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for IMITREX tablets and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition. Clinical Considerations Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX tablets. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. IMITREX tablets are not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated IMITREX nasal spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack.

c Use Safety and effectiveness in pediatric patients have not been established. IMITREX tablets are not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated IMITREX nasal spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of IMITREX nasal spray compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not establish the efficacy of oral IMITREX compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age‑dependent, with younger patients reporting reactions more commonly than older adolescents. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14‑year‑old male following the use of oral IMITREX; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal IMITREX are not presently available. 8.5 Geriatric Use Clinical trials of IMITREX tablets did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX tablets [see Warnings and Precautions (5.1)] . 8.6 Hepatic Impairment The maximum single dose in patients with mild to moderate hepatic impairment should not exceed 50 mg. IMITREX tablets are contraindicated in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)] .

8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal (see Data) . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data: The Sumatriptan/Naratriptan/TREXIMET (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group.

edical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Animal Data: Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 (approximately 2 times the MRHD on a mg/m 2 basis) and 0.75 mg/kg/day, respectively. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 2 times the MRHD on a mg/m 2 basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 3 times the MRHD on a mg/m 2 basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 5 times the MRHD on a mg/m 2 basis.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. IMITREX tablets are not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated IMITREX nasal spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of IMITREX nasal spray compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not establish the efficacy of oral IMITREX compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age‑dependent, with younger patients reporting reactions more commonly than older adolescents. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14‑year‑old male following the use of oral IMITREX; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal IMITREX are not presently available.

8.5 Geriatric Use Clinical trials of IMITREX tablets did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX tablets [see Warnings and Precautions (5.1)] .

10 OVERDOSAGE Patients in clinical trials (N = 670) received single oral doses of 140 to 300 mg without significant adverse reactions. Volunteers (N = 174) received single oral doses of 140 to 400 mg without serious adverse reactions. Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation. The elimination half-life of sumatriptan is approximately 2.5 hours [see Clinical Pharmacology (12.3)] , and therefore monitoring of patients after overdose with IMITREX tablets should continue for at least 12 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

11 DESCRIPTION IMITREX tablets contain sumatriptan succinate, a selective 5‑HT 1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The empirical formula is C 14 H 21 N 3 O 2 S•C 4 H 6 O 4 , representing a molecular weight of 413.5. Sumatriptan succinate is a white to off‑white powder that is readily soluble in water and in saline. Each IMITREX tablet for oral administration contains 35, 70, or 140 mg of sumatriptan succinate equivalent to 25, 50, or 100 mg of sumatriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate. Each 100-mg tablet also contains hypromellose, iron oxide, titanium dioxide, and triacetin. Imitrex Tablets chemical structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5‑HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5‑HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro‑inflammatory neuropeptide release. 12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)] . Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan’s development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate. 12.3 Pharmacokinetics Absorption The mean maximum concentration following oral dosing with 25 mg is 18 ng/mL (range: 7 to 47 ng/mL) and 51 ng/mL (range: 28 to 100 ng/mL) following oral dosing with 100 mg of sumatriptan. This compares with a C max of 5 and 16 ng/mL following dosing with a 5- and 20‑mg intranasal dose, respectively. The mean C max following a 6‑mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The bioavailability is approximately 15%, primarily due to presystemic metabolism and partly due to incomplete absorption. The C max is similar during a migraine attack and during a migraine‑free period, but the T max is slightly later during the attack, approximately 2.5 hours compared with 2.0 hours. When given as a single dose, sumatriptan displays dose proportionality in its extent of absorption (area under the curve [AUC]) over the dose range of 25 to 200 mg, but the C max after 100 mg is approximately 25% less than expected (based on the 25‑mg dose). Effect of Food: A food effect trial involving administration of IMITREX tablets 100 mg to healthy volunteers under fasting conditions and with a high‑fat meal indicated that the Cmax and AUC were increased by 15% and 12%, respectively, when administered in the fed state. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The apparent volume of distribution is 2.7 L/kg. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination The elimination half-life of sumatriptan is approximately 2.5 hours. Radiolabeled 14 C-sumatriptan administered orally is largely renally excreted (about 60%) with about 40% found in the feces. Most of the radiolabeled compound excreted in the urine is the major metabolite, IAA, which is inactive, or the IAA glucuronide. Only 3% of the dose can be recovered as unchanged sumatriptan.

rs. Radiolabeled 14 C-sumatriptan administered orally is largely renally excreted (about 60%) with about 40% found in the feces. Most of the radiolabeled compound excreted in the urine is the major metabolite, IAA, which is inactive, or the IAA glucuronide. Only 3% of the dose can be recovered as unchanged sumatriptan. Specific Populations Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Patients with Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined. Patients with Hepatic Impairment: The liver plays an important role in the presystemic clearance of orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration may be markedly increased in patients with liver disease. In one small trial of patients with moderate liver impairment (n = 8) matched for sex, age, and weight with healthy subjects (n = 8), the hepatically-impaired patients had an approximately 70% increase in AUC and C max and a T max 40 minutes earlier compared with the healthy subjects. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied. The use of IMITREX tablets in this population is contraindicated [see Contraindications (4), Use in Specific Populations (8.6)] . Male and Female Patients: In a trial comparing females to males, no pharmacokinetic differences were observed between genders for AUC, C max , T max , and half‑life. Racial Groups: The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Oral sumatriptan has not been evaluated for race differences. Drug Interaction Studies Monoamine Oxidase-A Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels [see Contraindications (4), Drug Interactions (7.2)] . Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the MAO inhibitors with subcutaneous sumatriptan. In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life. A small trial evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure. Alcohol: Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5‑HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5‑HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro‑inflammatory neuropeptide release.

12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)] . Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan’s development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

12.3 Pharmacokinetics Absorption The mean maximum concentration following oral dosing with 25 mg is 18 ng/mL (range: 7 to 47 ng/mL) and 51 ng/mL (range: 28 to 100 ng/mL) following oral dosing with 100 mg of sumatriptan. This compares with a C max of 5 and 16 ng/mL following dosing with a 5- and 20‑mg intranasal dose, respectively. The mean C max following a 6‑mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The bioavailability is approximately 15%, primarily due to presystemic metabolism and partly due to incomplete absorption. The C max is similar during a migraine attack and during a migraine‑free period, but the T max is slightly later during the attack, approximately 2.5 hours compared with 2.0 hours. When given as a single dose, sumatriptan displays dose proportionality in its extent of absorption (area under the curve [AUC]) over the dose range of 25 to 200 mg, but the C max after 100 mg is approximately 25% less than expected (based on the 25‑mg dose). Effect of Food: A food effect trial involving administration of IMITREX tablets 100 mg to healthy volunteers under fasting conditions and with a high‑fat meal indicated that the Cmax and AUC were increased by 15% and 12%, respectively, when administered in the fed state. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The apparent volume of distribution is 2.7 L/kg. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination The elimination half-life of sumatriptan is approximately 2.5 hours. Radiolabeled 14 C-sumatriptan administered orally is largely renally excreted (about 60%) with about 40% found in the feces. Most of the radiolabeled compound excreted in the urine is the major metabolite, IAA, which is inactive, or the IAA glucuronide. Only 3% of the dose can be recovered as unchanged sumatriptan. Specific Populations Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Patients with Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined. Patients with Hepatic Impairment: The liver plays an important role in the presystemic clearance of orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration may be markedly increased in patients with liver disease. In one small trial of patients with moderate liver impairment (n = 8) matched for sex, age, and weight with healthy subjects (n = 8), the hepatically-impaired patients had an approximately 70% increase in AUC and C max and a T max 40 minutes earlier compared with the healthy subjects. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied. The use of IMITREX tablets in this population is contraindicated [see Contraindications (4), Use in Specific Populations (8.6)] .

rease in AUC and C max and a T max 40 minutes earlier compared with the healthy subjects. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied. The use of IMITREX tablets in this population is contraindicated [see Contraindications (4), Use in Specific Populations (8.6)] . Male and Female Patients: In a trial comparing females to males, no pharmacokinetic differences were observed between genders for AUC, C max , T max , and half‑life. Racial Groups: The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Oral sumatriptan has not been evaluated for race differences. Drug Interaction Studies Monoamine Oxidase-A Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels [see Contraindications (4), Drug Interactions (7.2)] . Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the MAO inhibitors with subcutaneous sumatriptan. In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life. A small trial evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure. Alcohol: Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). There was no evidence in either species of an increase in tumors related to sumatriptan administration. Plasma exposures (AUC) at the highest doses tested were 20 and 8 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day. Mutagenesis Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day (less than the MRHD on a mg/m 2 basis). It is not clear whether this finding was due to an effect on males or females or both. When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day. 13.2 Animal Toxicology and/or Pharmacology Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60‑week study. Earlier examinations for these toxicities were not conducted and no‑effect doses were not established. Plasma exposure at the lowest dose tested was approximately 2 times that in humans at the MRHD.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). There was no evidence in either species of an increase in tumors related to sumatriptan administration. Plasma exposures (AUC) at the highest doses tested were 20 and 8 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day. Mutagenesis Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day (less than the MRHD on a mg/m 2 basis). It is not clear whether this finding was due to an effect on males or females or both. When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day.

13.2 Animal Toxicology and/or Pharmacology Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60‑week study. Earlier examinations for these toxicities were not conducted and no‑effect doses were not established. Plasma exposure at the lowest dose tested was approximately 2 times that in humans at the MRHD.

14 CLINICAL STUDIES The efficacy of IMITREX tablets in the acute treatment of migraine headaches was demonstrated in 3 randomized, double-blind, placebo-controlled trials. Patients enrolled in these 3 trials were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range: 18 to 65 years). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of IMITREX tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache. Acetaminophen was offered to patients in Trials 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or had worsened. Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 trials. The frequency and time to use of these additional treatments were also determined. In all trials, doses of 25, 50, and 100 mg were compared with placebo in the treatment of migraine attacks. In 1 trial, doses of 25, 50, and 100 mg were also compared with each other. In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving IMITREX tablets at all doses compared with those who received placebo. In 1 of the 3 trials, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50-mg or 100-mg group when compared with the 25-mg dose groups. There were no statistically significant differences between the 50-mg and 100-mg dose groups in any trial. The results from the 3 controlled clinical trials are summarized in Table 2. Table 2. Percentage of Patients with Headache Response (Mild or No Headache) 2 and 4 Hours following Treatment IMITREX Tablets 25 mg IMITREX Tablets 50 mg IMITREX Tablets 100 mg Placebo 2 h 4 h 2 h 4 h 2 h 4 h 2 h 4 h Trial 1 52% a 67% a 61% a,b 78% a,b 62% a,b 79% a,b 27% 38% (n = 298) (n = 296) (n = 296) (n = 94) Trial 2 52% a 70% a 50% a 68% a 56% a 71% a 26% 38% (n = 66) (n = 62) (n = 66) (n = 65) Trial 3 52% a 65% a 54% a 72% a 57% a 78% a 17% 19% (n = 48) (n = 46) (n = 46) (n = 47) a P <0.05 in comparison with placebo. b P <0.05 in comparison with 25 mg. The estimated probability of achieving an initial headache response over the 4 hours following treatment in pooled Trials 1, 2, and 3 is depicted in Figure 1. Figure 1. Estimated Probability of Achieving Initial Headache Response within 4 Hours of Treatment in Pooled Trials 1, 2, and 3 a a The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with oral sumatriptan. The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy. Kaplan‑Meier plot with patients not achieving response and/or taking rescue within 240 minutes censored to 240 minutes. For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Trial 1) and at 4 hours (Trials 1, 2, and 3) following administration of IMITREX tablets compared with placebo.

r taking rescue within 240 minutes censored to 240 minutes. For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Trial 1) and at 4 hours (Trials 1, 2, and 3) following administration of IMITREX tablets compared with placebo. As early as 2 hours in Trials 2 and 3, or as early as 4 hours in Trial 1, through 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. Figure 2. The Estimated Probability of Patients Taking a Second Dose of IMITREX Tablets or Other Medication to Treat Migraine over the 24 Hours following the Initial Dose of Study Treatment in Pooled Trials 1, 2, and 3 a a Kaplan‑Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within 2 hours postdose. There is evidence that doses above 50 mg do not provide a greater effect than 50 mg. There was no evidence to suggest that treatment with IMITREX tablets was associated with an increase in the severity of recurrent headaches. The efficacy of IMITREX tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on efficacy. Figure 1 Figure 2

<table width="100%"><col width="10%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="8%"/><col width="8%"/><tbody><tr><td styleCode="Rrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">IMITREX Tablets</content></paragraph><paragraph><content styleCode="bold">25 mg</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">IMITREX Tablets</content></paragraph><paragraph><content styleCode="bold">50 mg</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">IMITREX Tablets</content></paragraph><paragraph><content styleCode="bold">100 mg</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"/><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">2 h</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">4 h</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">2 h</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">4 h</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">2 h</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">4 h</content></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">2 h</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">4 h</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Trial 1</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>52%^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>67%^a</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>61%^a,b</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>78%^a,b</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>62%^a,b</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>79%^a,b</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>38%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 298)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 296)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 296)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 94)</paragraph></td></tr><tr><td styleCo

"Rrule Lrule Botrule " valign="top"><paragraph>(n = 296)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 296)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 94)</paragraph></td></tr><tr><td styleCo de="Rrule Lrule " valign="top"><paragraph>Trial 2</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>52%^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>70%^a</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>50%^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>68%^a</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>56%^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>71%^a</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>38%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 66)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 62)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 66)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(n = 65)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Trial 3</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>52%^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>65%^a</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>54%^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>72%^a</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>57%^a</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>78%^a</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>(n = 48)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>(n = 46)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>(n = 46)</paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>(n = 47)</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING IMITREX tablets, 25 mg, 50 mg, and 100 mg of sumatriptan (base) as the succinate. IMITREX tablets, 25 mg, are white, triangular‑shaped, film‑coated tablets debossed with “I” on one side and “25” on the other in blister packs of 9 tablets (NDC 0173-0735-00). IMITREX tablets, 50 mg, are white, triangular‑shaped, film‑coated tablets debossed with “IMITREX 50” on one side and a chevron shape (^) on the other in blister packs of 9 tablets (NDC 0173-0736-01). IMITREX tablets, 100 mg, are pink, triangular‑shaped, film‑coated tablets debossed with “IMITREX 100” on one side and a chevron shape (^) on the other in blister packs of 9 tablets (NDC 0173-0737-01). Store between 2°C and 30°C (36°F and 86°F).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events Inform patients that IMITREX tablets may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)] . Anaphylactic/Anaphylactoid Reactions Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX tablets. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4), Warnings and Precautions (5.9)] . Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of IMITREX tablets within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.3)] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the use of IMITREX tablets or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7), Drug Interactions (7.4)]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations (8.1)] . Lactation Advise breastfeeding women that they may develop transient breast pain when taking IMITREX. Advise breastfeeding women that avoiding breastfeeding for 12 hours after treatment with IMITREX can minimize their infant’s exposure to sumatriptan [see Use in Specific Populations (8.2)] . Ability to Perform Complex Tasks Treatment with IMITREX tablets may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of IMITREX tablets. IMITREX is a trademark owned by or licensed to the GSK group of companies. The other brand listed is a trademark owned by or licensed to its owner and is not owned by or licensed to the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products. Distributed by: GlaxoSmithKline Durham, NC 27701 ©2025 GSK group of companies or its licensor. IMT:9PI

PATIENT INFORMATION IMITREX (IM-i-trex) (sumatriptan) tablets What is the most important information I should know about IMITREX? IMITREX can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking IMITREX and get emergency medical help right away if you have any of the following symptoms of a heart attack: • discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back • severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw • pain or discomfort in your arms, back, neck, jaw, or stomach • shortness of breath with or without chest discomfort • breaking out in a cold sweat • nausea or vomiting • feeling lightheaded IMITREX is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you: • have high blood pressure • have high cholesterol levels • smoke • are overweight • have diabetes • have a family history of heart disease What is IMITREX? IMITREX is a prescription medicine used to treat acute migraine headaches with or without aura in adults. IMITREX is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines. IMITREX is not used to prevent or decrease the number of migraine headaches you have. It is not known if IMITREX is safe and effective to treat cluster headaches. It is not known if IMITREX is safe and effective in children under 18 years of age. Do not take IMITREX if you have: • heart problems or a history of heart problems • narrowing of blood vessels to your legs, arms, stomach, or kidneys (peripheral vascular disease) • uncontrolled high blood pressure • severe liver problems • hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider. • had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation • taken any of the following medicines in the last 24 hours: o almotriptan (AXERT) o frovatriptan (FROVA) o rizatriptan (MAXALT, MAXALT-MLT) o ergotamines (CAFERGOT, ERGOMAR, MIGERGOT) o eletriptan (RELPAX) o naratriptan (AMERGE) o sumatriptan and naproxen (TREXIMET) o dihydroergotamine (D.H.E. 45, MIGRANAL) Ask your healthcare provider if you are not sure if your medicine is listed above. • an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of this leaflet for a complete list of ingredients in IMITREX. Before you take IMITREX, tell your healthcare provider about all of your medical conditions, including if you: • have high blood pressure. • have high cholesterol. • have diabetes. • smoke. • are overweight. • have heart problems or family history of heart problems or stroke. • have kidney problems. • have liver problems. • have had epilepsy or seizures. • are not using effective birth control. • are pregnant or plan to become pregnant. It is not known if IMITREX can harm your unborn baby. • are breastfeeding or plan to breastfeed. IMITREX passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take IMITREX. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take IMITREX. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. IMITREX and certain other medicines can affect each other, causing serious side effects. Especially tell your healthcare provider if you take antidepressant medicines called: • selective serotonin reuptake inhibitors (SSRIs) • serotonin norepinephrine reuptake inhibitors (SNRIs) • tricyclic antidepressants (TCAs) • monoamine oxidase inhibitors (MAOIs) Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I take IMITREX? • Certain people should take their first dose of IMITREX in their healthcare provider’s office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting. • Take IMITREX exactly as your healthcare provider tells you to take it. • Your healthcare provider may change your dose. Do not change your dose without first talking to your healthcare provider. • Take IMITREX tablets whole with water or other liquids. • If you do not get any relief after your first tablet, do not take a second tablet without first talking with your healthcare provider. • If your headache comes back or you only get some relief from your headache, you can take a second tablet 2 hours after the first tablet. • Do not take more than 200 mg of IMITREX tablets in a 24‑hour period. • If you take too much IMITREX, call your healthcare provider or go to the nearest hospital emergency room right away. • You should write down when you have headaches and when you take IMITREX so you can talk with your healthcare provider about how IMITREX is working for you. What should I avoid while taking IMITREX? IMITREX can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert. What are the possible side effects of IMITREX? IMITREX may cause serious side effects. See “What is the most important information I should know about IMITREX?” These serious side effects include: • changes in color or sensation in your fingers and toes (Raynaud’s syndrome) • stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include: o sudden or severe stomach pain o stomach pain after meals o weight loss o fever o nausea or vomiting o constipation or diarrhea o bloody diarrhea • problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include: o cramping and pain in your legs or hips o feeling of heaviness or tightness in your leg muscles o burning or aching pain in your feet or toes while resting o numbness, tingling, or weakness in your legs o cold feeling or color changes in 1 or both legs or feet • medication overuse headaches. Some people who use too many IMITREX tablets may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX. • serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs.

ion overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX. • serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome: o mental changes such as seeing things that are not there (hallucinations), agitation, or coma o fast heartbeat o changes in blood pressure o high body temperature o tight muscles o trouble walking • hives (itchy bumps); swelling of your tongue, mouth, or throat. • seizures. Seizures have happened in people taking IMITREX who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take IMITREX. The most common side effects of IMITREX tablets include: • tingling or numbness in your fingers or toes • warm or cold feeling • feeling weak, drowsy, or tired • pain, discomfort, or stiffness in your neck, throat, jaw, or chest • dizziness Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of IMITREX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store IMITREX Tablets? Store IMITREX between 36°F to 86°F (2°C to 30°C). Keep IMITREX and all medicines out of the reach of children. General information about the safe and effective use of IMITREX. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use IMITREX for a condition for which it was not prescribed. Do not give IMITREX to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about IMITREX. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about IMITREX that is written for healthcare professionals. For more information, call 1-888-825-5249. What are the ingredients in IMITREX Tablets? Active ingredient: sumatriptan succinate Inactive ingredients: croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate 100‑mg tablets also contain hypromellose, iron oxide, titanium dioxide, and triacetin. IMITREX and AMERGE are owned by or licensed to the GSK group of companies. The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products. Distributed by: GlaxoSmithKline Durham, NC 27701 ©2024 GSK group of companies or its licensor. IMT:8PIL This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: February 2024

<table width="100%"><col width="8%"/><col width="30%"/><col width="62%"/><tbody><tr><td align="center" colspan="3" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PATIENT INFORMATION</content></paragraph><paragraph><content styleCode="bold">IMITREX (IM-i-trex)</content></paragraph><paragraph><content styleCode="bold">(sumatriptan)</content></paragraph><paragraph><content styleCode="bold">tablets</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about IMITREX?</content></paragraph><paragraph><content styleCode="bold">IMITREX can cause serious side effects, including:</content></paragraph><paragraph><content styleCode="bold">Heart attack and other heart problems. Heart problems may lead to death.</content></paragraph><paragraph><content styleCode="bold">Stop taking IMITREX and get emergency medical help right away if you have any of the following symptoms of a heart attack:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back</item><item><caption>&#x2022;</caption>severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw</item><item><caption>&#x2022;</caption>pain or discomfort in your arms, back, neck, jaw, or stomach</item><item><caption>&#x2022;</caption>shortness of breath with or without chest discomfort</item><item><caption>&#x2022;</caption>breaking out in a cold sweat</item><item><caption>&#x2022;</caption>nausea or vomiting</item><item><caption>&#x2022;</caption>feeling lightheaded</item></list><paragraph>IMITREX is not for people with risk factors for heart disease unless a heart exam is done and shows no problem.

/item><item><caption>&#x2022;</caption>breaking out in a cold sweat</item><item><caption>&#x2022;</caption>nausea or vomiting</item><item><caption>&#x2022;</caption>feeling lightheaded</item></list><paragraph>IMITREX is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have high blood pressure</item><item><caption>&#x2022;</caption>have high cholesterol levels</item><item><caption>&#x2022;</caption>smoke</item><item><caption>&#x2022;</caption>are overweight</item><item><caption>&#x2022;</caption>have diabetes</item><item><caption>&#x2022;</caption>have a family history of heart disease</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is IMITREX?</content></paragraph><paragraph>IMITREX is a prescription medicine used to treat acute migraine headaches with or without aura in adults.</paragraph><paragraph>IMITREX is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines.</paragraph><paragraph>IMITREX is not used to prevent or decrease the number of migraine headaches you have.</paragraph><paragraph>It is not known if IMITREX is safe and effective to treat cluster headaches.</paragraph><paragraph>It is not known if IMITREX is safe and effective in children under 18 years of age.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Do not take IMITREX if you have:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>heart problems or a history of heart problems</item><item><caption>&#x2022;</caption>narrowing of blood vessels to your legs, arms, stomach, or kidneys (peripheral vascular disease)</item><item><caption>&#x2022;</caption>uncontrolled high blood pressure</item><item><caption>&#x2022;</caption>severe liver problems</item><item><caption>&#x2022;</caption>hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.</item><item><caption>&#x2022;</caption>had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation</item><item><caption>&#x2022;</caption>taken any of the following medicines in the last 24 hours:</item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>o</caption>almotriptan (AXERT)</item><item><caption>o</caption>frovatriptan (FROVA)</item><item><caption>o</caption>rizatriptan (MAXALT, MAXALT-MLT)</item><item><caption>o</caption>ergotamines (CAFERGOT, ERGOMAR, MIGERGOT)</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>o</caption>eletriptan (RELPAX)</item><item><caption>o</caption>naratriptan (AMERGE)</item><item><caption>o</caption>sumatriptan and naproxen (TREXIMET)</item><item><caption>o</caption>dihydroergotamine (D.H.E. 45, MIGRANAL)</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Ask your healthcare provider if you are not sure if your medicine is listed above.</item><item><caption>&#x2022;</caption>an allergy to sumatriptan or any of the ingredients in IMITREX.

></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Ask your healthcare provider if you are not sure if your medicine is listed above.</item><item><caption>&#x2022;</caption>an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of this leaflet for a complete list of ingredients in IMITREX.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Before you take IMITREX, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have high blood pressure.</item><item><caption>&#x2022;</caption>have high cholesterol.</item><item><caption>&#x2022;</caption>have diabetes.</item><item><caption>&#x2022;</caption>smoke.</item><item><caption>&#x2022;</caption>are overweight.</item><item><caption>&#x2022;</caption>have heart problems or family history of heart problems or stroke.</item><item><caption>&#x2022;</caption>have kidney problems.</item><item><caption>&#x2022;</caption>have liver problems.</item><item><caption>&#x2022;</caption>have had epilepsy or seizures.</item><item><caption>&#x2022;</caption>are not using effective birth control.</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. It is not known if IMITREX can harm your unborn baby.</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. IMITREX passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take IMITREX.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>IMITREX and certain other medicines can affect each other, causing serious side effects.</paragraph><paragraph><content styleCode="bold">Especially tell your healthcare provider if</content> you take antidepressant medicines called:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>selective serotonin reuptake inhibitors (SSRIs)</item><item><caption>&#x2022;</caption>serotonin norepinephrine reuptake inhibitors (SNRIs)</item><item><caption>&#x2022;</caption>tricyclic antidepressants (TCAs)</item><item><caption>&#x2022;</caption>monoamine oxidase inhibitors (MAOIs)</item></list><paragraph>Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.</paragraph><paragraph>Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take IMITREX?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Certain people should take their first dose of IMITREX in their healthcare provider&#x2019;s office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting. </item><item><caption>&#x2022;</caption>Take IMITREX exactly as your healthcare provider tells you to take it.</item><item><caption>&#x2022;</caption>Your healthcare provider may change your dose.

office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting. </item><item><caption>&#x2022;</caption>Take IMITREX exactly as your healthcare provider tells you to take it.</item><item><caption>&#x2022;</caption>Your healthcare provider may change your dose. Do not change your dose without first talking to your healthcare provider.</item><item><caption>&#x2022;</caption>Take IMITREX tablets whole with water or other liquids.</item><item><caption>&#x2022;</caption>If you do not get any relief after your first tablet, do not take a second tablet without first talking with your healthcare provider.</item><item><caption>&#x2022;</caption>If your headache comes back or you only get some relief from your headache, you can take a second tablet 2 hours after the first tablet.</item><item><caption>&#x2022;</caption>Do not take more than 200 mg of IMITREX tablets in a 24&#x2011;hour period.</item><item><caption>&#x2022;</caption>If you take too much IMITREX, call your healthcare provider or go to the nearest hospital emergency room right away.</item><item><caption>&#x2022;</caption>You should write down when you have headaches and when you take IMITREX so you can talk with your healthcare provider about how IMITREX is working for you.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I avoid while taking IMITREX?</content></paragraph><paragraph>IMITREX can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of IMITREX?</content></paragraph><paragraph><content styleCode="bold">IMITREX may cause serious side effects.</content> See &#x201C;What is the most important information I should know about IMITREX?&#x201D;</paragraph><paragraph>These serious side effects include:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>changes in color or sensation in your fingers and toes (Raynaud&#x2019;s syndrome)</item><item><caption>&#x2022;</caption>stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include:</item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="unordered"><item><caption>o</caption>sudden or severe stomach pain</item><item><caption>o</caption>stomach pain after meals</item><item><caption>o</caption>weight loss</item><item><caption>o</caption>fever</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>o</caption>nausea or vomiting</item><item><caption>o</caption>constipation or diarrhea</item><item><caption>o</caption>bloody diarrhea</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include:<list listType="unordered"><item><caption>o</caption>cramping and pain in your legs or hips</item><item><caption>o</caption>feeling of heaviness or tightness in your leg muscles</item><item><caption>o</caption>burning or aching pain in your feet or toes while resting</item><item><caption>o</caption>numbness, tingling, or weakness in your legs</item><item><caption>o</caption>cold feeling or color changes in 1 or both legs or feet</item></list></item><item><caption>&#x2022;</caption>medication overuse headaches.

ion>o</caption>burning or aching pain in your feet or toes while resting</item><item><caption>o</caption>numbness, tingling, or weakness in your legs</item><item><caption>o</caption>cold feeling or color changes in 1 or both legs or feet</item></list></item><item><caption>&#x2022;</caption>medication overuse headaches. Some people who use too many IMITREX tablets may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX.</item><item><caption>&#x2022;</caption>serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs.</item><item><caption> </caption>Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome:<list listType="ordered"><item><caption>o</caption>mental changes such as seeing things that are not there (hallucinations), agitation, or coma</item><item><caption>o</caption>fast heartbeat</item><item><caption>o</caption>changes in blood pressure</item><item><caption>o</caption>high body temperature</item><item><caption>o</caption>tight muscles</item><item><caption>o</caption>trouble walking</item></list></item><item><caption>&#x2022;</caption>hives (itchy bumps); swelling of your tongue, mouth, or throat.</item><item><caption>&#x2022;</caption>seizures. Seizures have happened in people taking IMITREX who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take IMITREX.</item></list><paragraph>The most common side effects of IMITREX tablets include:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>tingling or numbness in your fingers or toes</item><item><caption>&#x2022;</caption>warm or cold feeling</item><item><caption>&#x2022;</caption>feeling weak, drowsy, or tired</item><item><caption>&#x2022;</caption>pain, discomfort, or stiffness in your neck, throat, jaw, or chest</item><item><caption>&#x2022;</caption>dizziness</item></list><paragraph>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</paragraph><paragraph>These are not all the possible side effects of IMITREX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store IMITREX Tablets?</content></paragraph><paragraph>Store IMITREX between 36&#xB0;F to 86&#xB0;F (2&#xB0;C to 30&#xB0;C).</paragraph><paragraph><content styleCode="bold">Keep IMITREX and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of IMITREX.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use IMITREX for a condition for which it was not prescribed. Do not give IMITREX to other people, even if they have the same symptoms you have. It may harm them.</paragraph><paragraph>This Patient Information leaflet summarizes the most important information about IMITREX. If you would like more information, talk with your healthcare provider.

on for which it was not prescribed. Do not give IMITREX to other people, even if they have the same symptoms you have. It may harm them.</paragraph><paragraph>This Patient Information leaflet summarizes the most important information about IMITREX. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about IMITREX that is written for healthcare professionals.</paragraph><paragraph>For more information, call 1-888-825-5249.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in IMITREX Tablets?</content></paragraph><paragraph>Active ingredient: sumatriptan succinate</paragraph><paragraph>Inactive ingredients: croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate</paragraph><paragraph>100&#x2011;mg tablets also contain hypromellose, iron oxide, titanium dioxide, and triacetin.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>IMITREX and AMERGE are owned by or licensed to the GSK group of companies. The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.</paragraph><paragraph>Distributed by:</paragraph><paragraph>GlaxoSmithKline</paragraph><paragraph>Durham, NC 27701</paragraph><paragraph>&#xA9;2024 GSK group of companies or its licensor.</paragraph><paragraph>IMT:8PIL</paragraph></td></tr></tbody></table>